Week 10 Hematology Disorders F2024 Student Final PDF

ALTERATIO NS OF HEMATOLO GIC FUNCTION PAT401 Week 10 Fall 2024 1  Disorders Involve either insufficient or excessive numbers of erythrocytes in circulation or normal Involve numbers of cells with abnormal components Erythrocyte Disorders involving W...

ALTERATIO NS OF HEMATOLO GIC FUNCTION PAT401 Week 10 Fall 2024 1  Disorders Involve either insufficient or excessive numbers of erythrocytes in circulation or normal Involve numbers of cells with abnormal components Erythrocyte Disorders involving WBCs range from increased s, numbers of leukocytes (leukocytosis) in response to infections, or proliferative disorders Leukocytes, (i.e. leukemia), to decreased numbers of leukocytes (i.e. leukopenia) Platelets Several disease states increase or decrease clotting in at least one of three main components of the clotting process Erythrocyte Disorders 3 Hematology Values Erythrocyte (RBC count) 4.2-6.1 x 1012/L Hematocrit 0.40-0.54g/L Hemoglobin 7.4-11.2 mmol/L ALTERATIONS OF HEMATOLOGIC FUNCTION – SICKLE CELL DISEASE  Affects millions of people worldwide Most common among persons with ancestry from sub-Saharan Africa Also present among individuals with ancestry from Mediterranean countries, Arabian Peninsula, parts of India, and Spanish-speaking areas of South America Sickle Group of autosomal recessive disorders Sickle cell anemia (HbS) Cell Most severe! Sickle cell-thalassemia disease Disease Sickle cell-HbC disease Sickling is an occasional, intermittent phenomenon Decreased oxygen (PO2) of the blood (hypoxemia) Increased hydrogen ion concentration in the blood (decreased pH) Increased plasma osmolality, decreased plasma volume, and low temperature Scanning Electron Micrograph of Normal and Sickle-Shaped Red Blood Cells Together Abnormal hemoglobin in RBCs Hemoglobin S (HbS: sickle hemoglobin) Polymerization Sickled RBCs stiffen and stretch into elongated sickle shape Change from a flexible, beneficial cell to inflexible one Causes hypoxia and damages tissues Figure 30.3, Rogers, 2023, 7 p. 997  Sickling of Erythrocytes 8 Figure 30.4, Rogers, 2023,  Membrane derangements occur because as HbS units (polymers) grow they protrude through membrane skeleton causing How Sickling changes in membrane structure Membrane derangement leads to Causes changes in ionic flow with an influx in Ca++ and an efflux of K+ Damage to and H2O Erythrocytes Damaged cells converted to end- stage, nondeformable or stiff and irreversibly sickled cells 9  Pathophysiology of Sickle Cell Disease During inflammatory Increase expression of adhesion molecules on endothelial cells reactions, leukocytes Prevents sickled RBCs’ movement through microvasculature release meditators Sickled RBCs express more Further prevents sickled RBCs’ movement through adhesion molecules and are microvasculature sticky Sluggish and stagnant RBCs Result in extended exposure to low oxygen, sickling, and vascular within inflamed vascular obstruction vessels Lysed sickle RBCs release Free hemoglobin inactivates nitric oxide hemoglobin Decrease in blood pH Leads to increasing fraction of deoxygenated HbS and reduces hemoglobin's predisposition to sickling affinity for oxygen As less oxygen is taken up PO2 drops, promoting additional sickling by hemoglobin in lungs 10  More About Sickle Cell Disease Figure 30.2, Rogers, 2023, 11 p. 996 What Do We Know About Sickling? Sickling usually not permanent Most sickled erythrocytes regain normal shape after reoxygenation, return of PO 2 to normal, and rehydration Irreversible sickling caused by permanent plasma membrane damage, which in turn is caused by sickling In clients with sickle cell anemia (erythrocytes contain high percentage of HbS - 75% to 95%), up to 30% of erythrocytes can become irreversibly sickled Extent, severity, and manifestations of sickling depend on percentage of hemoglobin that is HbS Homozygous inheritance of HbS produces severest form of SCD—sickle cell anemia Presence of sickle cell trait rarely results in sickling because clients also produce normal HbF and HbA which do not contribute to sickling But, anemia persists because HbF does not live 120 days 12 Sickle Cell Disease 13 Figure 30.5, Rogers, 2023, Use Your Clinical Judgement! Hemoglob in are irreversible structural increase the flexibility of alterations erythrocytes are stimulated by observed deoxygenation with sickle are stimulated by alkalosis cell disease: 14 Manifestations of Microvascular occlusions Sickle Cell Disease responsible for most serious and urgent manifestations! General Usually do not Two key attributes manifestations of appear until at contribute to Variable hemolytic anemia least 6 months of presentation from the sickling age process include Postnatal Mild symptoms to concentrations of Chronic disease Pallor, fatigue, repeated HbF decrease, with acute jaundice, vasoocclusive causing exacerbations irritability crises concentrations of HbS to rise Condition affecting RBCs suppling oxygen to all cells of body Can affect any 15 part of body! Manifestations 16 Figure 30.6, Rogers, 2023, Figure 30.7, Rogers, 2023,  Extensive sickling can precipitate four types of acute manifestations, Acute often referred to as crises Manifestatio ns: Four Vaso-occlusive crisis Types of Aplastic crisis Sequestration crisis Crises Hyperhemolytic crisis 17 Acute Manifestations: Four Types of Crises (cont.) What causes the severe Vasoocclusive crisis (pain crisis) pain? Sickling is in microcirculation, extremely painful, and symmetric Hands and feet exhibit painful swelling (hand-foot syndrome) Acute chest syndrome Sickled RBCs attach to endothelium of injured, underventilated, and inflamed lung and fail to be reoxygenated Aplastic crisis Transient cessation in RBC production occurs as a result of viral infection 18 Acute Sequestratio Hyperhemol Manifestatio n crisis ytic crisis ns: Four Types of Large Rate of RBC amounts of destruction Crises blood pool is (cont.) in spleen accelerated 19  Infection Most common cause of death More Glomerular disease Manifestations Hyposthenuria—inability of tubules of kidneys to concentrate of Sickle Cell urine Bed wetting, proteinuria Disease (cont.) Gallstones or cholecystitis 20 Prepregnancy Sickle Cell Test Figure 30.8, Rogers, 2023, 21 p. 1002  Most infants with sickle cell disease now identified by routine neonatal screening Parents’ hematologic history and clinical manifestations may suggest child has sickle cell disease Neonatal Hematologic tests necessary to confirm diagnosis If sickle test confirms presence of HbS, hemoglobin electrophoresis Screening performed to provide amount of HbS in erythrocytes Prenatal diagnosis can be made by chorionic villus sampling as early as 8 to 10 weeks’ gestation or by amniotic fluid analysis at 15 weeks’ gestation 22  Importance of Health Maintenance Activities Routine childhood immunizations, annual influenza vaccine, pneumococcal and meningococcal vaccines Children under 5 years of age may also be prescribed prophylactic penicillin Avoid fever, infection, acidosis, dehydration, constricting clothes, exposure to cold Seek immediate medical attention in event of fever Screen for Nephropathy HTN Retinopathy Pulmonary disease Risk of stroke 23 Treatment for Sickle Cell Disease Immediate Aggressive Oxygen Pain correction of antibiotic therapy To reverse hypoxia management Acidosis for Pain is very Dehydration Infections complex → multimodal management Hydroxyurea Transfusion Curative Causes increase in therapy treatments HbF concentration Can decrease Hematopoietic Anti-inflammatory morbidity and stem cell effect mortality transplantation and gene therapy 24  Emerging Science: Curative Treatments for Sickle Cell Disease Hematopoietic stem cell transplantation Gene therapy involves removal of some hematopoietic stem cells Allows for gene editing Stem cells then infused back into client Goal is to have cells express newly edited version of gene Gene therapy targets two genes Mutation in HBB results in production of HbS Gene editing causes correct hemoglobin to be produced BCL11A gene responsible for transition from fetal to adult hemoglobin Gene editing causes BCL11A to revert to 25 producing fetal hemoglobin instead of adult Pharmacother apy of Sickle Cell Disease/Sickle Cell Crises 26 Pharmacotherapy: Drug Classifications and Examples Classification Drug Opioids morphine hydromorphone NSAIDS ibuprofen naproxen Tricyclic amitriptyline antidepressants Antiepileptics gabapentin Antisickling agents hydroxyurea 27  28 Indications for use acute and severe chronic pain, acute MI pain, cancer pain Mechanisms of action binds with mu and kappa receptors in brain and dorsal horn of spinal cord mimics endogenous opioids such as endorphins and Opioids: enkephalins (also stimulate opioid receptors) Desired effects Morphine alters perception and emotional response to pain produces profound analgesic and euphoric effects Adverse effects dysphoria (restlessness, depression, anxiety) hallucinations nausea, constipation orthostatic hypotension, dizziness pruritus respiratory depression, cardiac arrest  29 Indications relief of moderate to severe pain Opioids: Mechanisms of action inhibits ascending pain pathways in CNS Hydromorphone increases pain threshold alters pain perception Desired effects analgesia Adverse effects Assess for re life-threatening respiratory depression! spiratory depression! hypotension When would drowsiness, dizziness, confusion yo u n o ti f y th e p r pruritus escriber? What is the a nausea, constipation ntidote to opioids? NOTE: HYDROMORPHONE IS ABOUT 5 TIMES MORE POTENT THAN MORPHINE! NSAIDS: Ibuprofen Indications relieve mild to moderate pain, fever, and inflammation Mechanisms of action inhibition of prostaglandin synthesis Desired effects reduction of pain, temperature, and inflammation Adverse effects nausea, heartburn, epigastric 30 NSAIDs: Naproxen Relief of minor aches and pains in muscles, bones, Indications joints Mechanisms of Inhibits COX-1, COX-2 action analgesic Desired effects anti-inflammatory antipyretic Adverse effects N/V, peptic ulcer, GI ulceration, bleeding 31  Tricyclic Antidepressants: Amitriptyline Indications: neuropathic pain (in addition to depression) Mechanisms of action: Inhibits the reuptake of norepinephrine and serotonin, and to a lesser extent dopamine, into presynaptic nerve terminals Desired effects: modulates ascending pain impulses. Decrease in neuropathic pain Adverse effects: Orthostatic hypotension, anticholinergic effects Figure 17.1 Adams et al., 2025, p. 224 32 32  Antiepileptics: Gabapentin Structurally related to inhibitory neurotransmitter gamma-aminobutyric acid (GABA) Indications: Adjunct treatment of seizures. Unlabeled uses: neuropathic pain Mechanisms of action: Stimulates an influx of chloride ions that interact with the GABA receptor-chloride channel complex  more GABA in synapse Desired effect: increases GABA (inhibitory transmitter) thus decreasing pain Adverse effects: somnolence, dizziness, Figure 21.3 Adams et al., 2025, p. 304 Mechanisms of action of anti-epileptic drugs that affect GABA (does ataxia, fatigue, nystagmus, weight gain, not include gabapentin) headache 33 Antisickling Agents: Hydroxyurea Indications (Sickle Cell Disease/Sickle Cell Crises) recurrent vaso-occlusive events; frequent painful episodes Mechanisms of action causes production of RBCs containing fetal hemoglobin Desired effects by increasing fetal hemoglobin, RBC sickling and destruction is reduced, and oxygen transport throughout body improved decreases likelihood of sickle hemoglobin polymerization, with subsequent sickling and RBC destruction reduces frequency of vaso-occlusive crises reduces need for blood transfusions Adverse effects bone marrow suppression (neutropenia, anemia, thrombocytopenia), elevation of hepatic enzymes (liver 34 damage), anorexia, N/V, thinning of the hair, darkening Leukocyte Disorders 35 Hematology Values Leukocyte (WBC count) 5-10 x 109/L Lymphocyte 1000-4000 x 106/L Monocyte & macrophage 100-700 x 106/L Eosinophil 50-500 x 106/L Neutrophil (segmented) 2500-8000 x 106/L Basophil 25-100 x 106/L  Alterations can occur in quantity and quality of leukocytes Alterations Leukocyte functioning affected of if too many or too few WBCs present in blood (quantitative Leukocyte alterations) Or if cells that are present are Function structurally or functionally defective (qualitative alterations) 37 Quantitative Versus Qualitative Alterations Quantitative alterations Qualitative alterations Increases or decreases in cell Disruption of leukocyte numbers function Decreased production in bone Phagocytic cells marrow or accelerated (granulocytes, monocytes, destruction of cells in macrophages) may lose circulation phagocytic capacity to Response to function Lymphocytes may lose infection/leukemias capacity to respond to antigens 38 Lymphoid Uncontrolled proliferation of malignant leukocytes Neoplasm: Disruption and overcrowding of bone marrow Leukemias Decreased production and function of normal hematopoietic cells Classification Predominant cell of origin Myeloid or lymphoid Rate of progression Acute or chronic Risk factors Environmental factors Genetic factors Other diseases Figure 29.12, Rogers, 2023, p. 948 39  Leukemia Arises From Stem-Like Cells A blood stem cell undergoes multiple steps to finally become a red blood cell, platelet, or white blood cell Figure 29.15, Rogers, 2023, p. 952 40  Pathophysiology: Common Features All leukemias have common pathophysiologic features Most lymphoid neoplasms arise from B-cell and T-cell differentiation pathways 85% to 90% of lymphoid neoplasms have B-cell origin Followed by T-cells Abnormal immature WBCs (leukemic blasts), fill bone marrow and can spill into blood Leukemic blasts “crowd out” bone marrow, compete for growth factors, and cause cellular proliferation of other cell lines to decrease or cease Figure 29.12, Rogers, 2023, p. 948 41  Common genetic abnormality 95% of chronic myelogenous Genetic leukemia (CML) 3% of acute myelogenous leukemia Connection (AML) 25% of adults with acute : lymphocytic leukemia (ALL) 10% of children with acute Philadelphi lymphocytic leukemia (ALL) a Mitotic error Chromoso Reciprocal translocation results in abnormal chromosome me Chromosomes 9 and 22 Results in expression of an oncoprotein, BCR-ABL1 Essential for transformation into leukemic cells Excessively activates intracellular pathways Promotes cell proliferation, decreases sensitivity to apoptosis Leukemic cells accumulate in blood, liver, spleen, lymph nodes, other organs Figure 29.14, Rogers, 2023, p. 950 42 Risk Factors for Leukemia Children Adults Prenatal x-ray exposure Chemical exposures Postnatal exposure to high- Chemotherapy dose radiation Ionizing radiation Exposure to cigarette Viral infections smoke (prenatal and postnatal) Parental exposure to pesticides and other environmental toxins before or during pregnancy Genetic mutations and conditions Siblings i.e., monozygotic 43 Leukemia Characterized by undifferentiated or immature cells Usually, blast cells Onset of disease Abrupt and rapid Without treatment Disease progression results in short survival time Four general types Acute myelogenous leukemia (AML) Acute lymphocytic leukemia (ALL) Chronic lymphocytic leukemia (CLL) Chronic myelogenous leukemia (CML) 44 Acute Leukemias: Two Types We Will Focus On! Acute myelogenous leukemia Acute lymphocytic leukemia (AML) (ALL) AKA AKA Acute myeloblastic leukemia Acute lymphoblastic leukemia More common acute Most common acute leukemia leukemia in adults in childhood Aggressive, fast-growing Aggressive, fast-growing 24% survival rate 91% survival rate Primary cell Primary cell Precursor myeloid cells Lymphoblasts and B cells Overproduction of myeloblasts Presence of undifferentiated or 45 immature lymphoblast cells  Manifestations of acute leukemia are similar t a r e Bone pain Wha g all Fatigue, pallor a u s in Bleeding, petechiae, purpura, c i g ns e se s ecchymosis th and ? Infection to m s Mouth, throat, respiratory sy m p tract, lower colon, urinary tract, skin Fever, chills Manifestations: Anorexia, weight loss, diminished sensitivity to sour AML & ALL and sweet tastes, muscle atrophy, difficulty swallowing Central nervous system (CNS) involvement H/A, vomiting, papilledema, facial palsy, blurred vision, auditory disturbances, meningeal irritation 46 Tests & Tests Peripheral blood smear; Treatment: bone marrow aspiration Accurate diagnosis AML & ALL essential because of differences in treatment and prognosis of ALL and AML Treatment Combination chemotherapy Radiation Supportive measures Blood transfusions, antibiotics, antifungals, antivirals Stem cell transplantation Figure 29.17, Rogers, 2023, p. 955 47  Consequence of leukemia and treatments! Anemia Treatment Blood products Neutropenia Myelosuppressi Treatment Granulocyte colony- on stimulated factor (G-CSF) Granulocyte-macrophage colony stimulating factor (GM-CSF) Low WBC count Treatment Colony-stimulating factors 48 ACUTE MYELOGENOUS LEUKEMIA (AML) 49  Age -related disease Median age at diagnosis approx. 70 years of age Rise in incidence 40 to 50 years of age Steep increase from 60 to 64 years of age Driver mutations in AML include four categories Transcription factor mutations that disrupt normal myeloid differentiation AML Mutation of signaling proteins that promote pro-growth/survival pathways Mutations of genes that regulate or maintain the epigenome Mutation of TP53 or genes that regulate p53 Can arise in people de novo, those with an underlying hematological disorder, or as a consequence of prior treatment Most frequently reported secondary cancer after high doses of chemotherapy for Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma, ovarian 50  Cellular Senescence Produces Pro-Tumorigenic Microenvironment Various stimuli lead to cellular senescence and accumulation in aged tissues Senescent state characterized by Activation of potent tumor suppressors p16INK4a and /or p53 Secretion of cytokines (IL-6, IL-8), growth factors (PDGF), matrix metalloproteinases (MMPs), extracellular vesicles (EVs) Irreversible arrest of cell proliferation and secretion of proinflammatory cytokines, chemokines, and growth factors, called senescence-associated secretory phenotype (SASP) Senescent response may have evolved to suppress development of cancer and assist tissue repair and regeneration But, senescent response may become maladaptive Figure 29.13, Rogers, 2023, p. 949 51  Pathophysiolo gy: AML Malignancy of stem cell precursors of myeloid lineage - RBCs, platelets, and WBCs (except B and T cells) Overproduction of neoplastic clonal myeloid stem cells or myeloblasts - immature white blood cells that are not lymphoblasts Results in accumulation of immature myeloid blasts in marrow and other organs Mutations may lead to proliferation by activating growth factor signaling and a decreased rate of apoptosis Bone marrow and blood show leukocytosis and predominance of blast cells Bone marrow crowding by blast cells produces marrow failure and complications, including 52 Figure 29.15, Rogers, 2023, p. 952 Blast Cells Acute Myeloid Leukemia Without Maturation Figure 30.10, Rogers, 2023, p. 53 ACUTE LYMPHOCYTI C LEUKEMIA (ALL) 54 ALL 75%–80% of all leukemias in children Children and Adults account for 20% of all cases adults over 50 But mortality rate is significantly higher Develops at Developed countries and higher different rates in socioeconomic categories have increased different incidence geographic Reason unclear locations Genetic susceptibility, environmental Unclear cause factors, viral infections 55  Pathophysiolo gy: ALL Progresses from malignant transformation of immature B- or T-cell progenitor cells (stem cell) As leukemia develops, bone marrow becomes dense with lymphoblasts that replace normal marrow and disrupt normal function Increase in lymphoblasts to more than 30% Many of the chromosomal abnormalities cause dysregulation of expression and function of transcription factors required for normal B-cell and T-cell development Figure 29.15, Rogers, 2023, p. 952 56 Use Your Clinical Judgement! A nurse recalls that acute lymphocytic leukemia: is most common in adults has a higher mortality rate in children compared with adults is defined as greater than 30% lymphoblasts in bone marrow is caused by abnormal proliferation of myeloid precursor cells 57 Platelet Disorders 58 Hematology Values Platelets 150-400 x 109/L  Hemostasis is dependent on adequate numbers of platelets and levels of coagulation Alterations factors of Platelets and Diminished hemostasis results Coagulatio in either internal or external n hemorrhage Excessive levels of coagulation factors can lead to defective hemostasis or spontaneous and unnecessary clotting 60  Quantitative Versus Qualitative Alterations Quantitative or qualitative abnormalities of platelets can interrupt normal blood coagulation and prevent hemostasis Can coexist Qualitative disorders affect structure or function of platelets Usually prevent platelet adherence and aggregation Adhesion between platelets and vessel wall Platelet-platelet adhesion Prevents formation of platelet plug Prolonged bleeding can result Quantitative abnormalities Thrombocytopenia - decrease in number of platelets Thrombocythemia - increase in number of platelets 61 Causes of Thrombocytopenia Decreased platelet production, increased destruction, or both May be congenital or acquired Acquired thrombocytopenia is more common May occur as result of decreased platelet production secondary to viral infections, drugs, nutritional deficiencies, chronic renal failure, bone marrow suppression, radiation therapy, or bone marrow infiltration by cancer Most common forms of thrombocytopenia are result of increased platelet destruction Disseminated intravascular coagulation is one example Spleen can also sequester too many platelet Normally stores about one-third of body’s platelets Dilutional thrombocytopenia After massive fluid resuscitation and massive blood transfusion 62  Defined as platelet count